Annelore Altendorf-Hofmann

FGFR1 expression and gene copy numbers in human lung cancer

FGFR1 is a receptor tyrosine kinase of which the ligands belong to the fibroblast growth factor family. To evaluate the significance of FGFR1 in lung cancer, we analysed tumours by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Tissue microarrays were constructed containing 380 lung cancer samples including squamous cell carcinomas (SCC), adenocarcinomas (ADC), non-small cell lung cancer not otherwise specified, metastases, neuroendocrine tumours, large cell lung cancer and small cell lung cancer. FGFR1 expression was analysed by IHC and scored semi-quantitatively by a four-tier approach (0, 1, 2, 3). Using dual-colour interphase FISH with probes specific for the locus on 8p12 and the centromere of chromosome 8 (CEN8), copy numbers of FGFR1 were determined. High expression of FGFR1 was associated with increased FGFR1 gene copy numbers in squamous cell carcinoma (p < 0.001). The FGFR1 locus was equally affected by copy number losses and gains. The higher FGFR1 gene copy numbers in SCC compared to ADC did not reach statistical significance. High copy number amplification of FGFR1 was a very rare event, the FGFR1/CEN8 signal ratio reaching a maximum value of 2.75. There were no significant associations between FGFR1 and clinicopathological parameters. Fibroblast growth factor signalling represents an interesting therapeutic target in lung cancer. However, the pathways are complex with potential oncogenic and anti-oncogenic activities. Our data may help to define criteria for selecting patients that may benefit from these new therapeutic options.

Loss of desmocollin 1-3 and homeobox genes PITX1 and CDX2 are associated with tumor progression and survival in colorectal carcinoma.

BackgroundGenomewide expression profiling has identified a number of genes differentially expressed in colorectal carcinomas (CRCs) compared to normal tissue. Some of these genes were linked to epithelial–mesenchymal transition. We tested whether genes including desmocollins and homeobox genes were distinct on the protein level and correlated the expression with clinicopathological data.MethodsTissue microarrays of 402 R0-resected colorectal carcinomas of UICC stage II or III were constructed to evaluate ten biomarkers. Furthermore, mRNA expression of desmocollins was evaluated in eight colon cancer cell lines. Demethylation test was performed by treatment with 5-aza-2´-deoxycytide in five colon cancer cell lines.ResultsOn protein level, high expression of desmocollin 1 (DSC1) was observed in 41.6%, DSC2 in 58.0%, DSC3 in 61.4%, E-cadherin in 71.4%, CDX2 in 58.0%, PITX1 in 55.0%, CDK4 in 0.2%, TLE1 in 1.3%, Factor H in 42.5%, and MDM2 in 0.2%. Reduced expression of DSC1-3 was statistically linked to higher grading and DSC2, E-cadherin and CDX2 with shorter survival in high-grade carcinomas. Multivariate analysis showed that pathological stage and low PITX1 expression were statistically associated with shorter patients survival. On mRNA level, seven out of eight cell lines exhibited no expression of DSC1, and four out of seven restored DSC1 expression after demethylation test.ConclusionsReduced expression of PITX1 was independently correlated to shorter patients survival and could serve as a prognostic marker. Decreased expression of DSC1-3 is significantly correlated with higher tumor grading. Downregulation of DSC1 could be explained by DNA hypermethylation in colon cancer cells.

Loss of p16(INK4a) is associated with reduced patient survival in soft tissue tumours, and indicates a senescence barrier

Aims p16(INK4a) is an important factor in carcinogenesis, and its expression is linked to oncogene-induced senescence. Very recently it was shown that upregulation and downregulation of p16 indicates a senescence barrier in the serrated route of colorectal cancer. However, in soft tissue sarcoma (STS), the senescence mechanism is still not understood. In this study, we analysed a well characterised cohort of STS for p16(INK4a) expression and correlated the results with clinicopathological parameters including survival. Methods Tissue microarrays (TMA) of 183 soft tissue and bone tumours were analysed immunohistochemically. Furthermore, mRNA expression of p16(INK4a) was evaluated in four sarcoma cell lines, and a demethylation test was performed by treatment with 5-aza-2′-deoxycytide. Results On protein level, expression of p16(INK4a) was observed in undifferentiated pleomorphic sarcoma (UPS) in 69.1%, leiomyosarcoma in 85.7%, synovial sarcoma in 77.8%, liposarcoma in 88.9%, angiosarcoma in 60.9% and MPNST in 22.2%. Loss of p16(INK4a) was observed in high grade sarcomas and showed a significant correlation with reduced patient survival (p=0.032). On DNA level, one out of four sarcoma cell lines exhibited a methylated p16(INK4a) promoter analysed by methylation-specific PCR. p16(INK4a) mRNA and protein expression was restored after demethylation using 5-aza-2′-deoxycytide. Conclusions Upregulation of p16(INK4a) might be associated with the induction of senescence and indicates a senescence barrier. Downregulation of p16(INK4a) is found in malignant progression, and is significantly correlated with reduced patient survival. Downregulation of p16(INK4a) may be explained by DNA-hypermethylation in sarcoma cells.

Update from the soft tissue tumour registry in Jena

The Jena Institute of Pathology has been serving as a consultation and reference center for soft tissue tumors in Germany since 1978. The present study provides an overview of the clinicopathological data from a two-year period and an update on diagnostics and research. Retrospectively, 7043 cases sent to the institute in the years 2006 and 2007 were analyzed. The majority of cases (>77.7%) were soft tissue tumors, of which 49% were categorized as malignant, 11.4% as intermediate, 35% as benign and 4.6% as tumors of uncertain biological potential. Neoplasms with fibroblastic differentiation were the most frequent. The mean age of patients with a sarcoma was 63 years. The molecular pathological analysis of soft tissue tumors has attained a major role in diagnosis. This is further advanced at the Jena institute in the context of a German Federal Ministry of Education and Research (BMBF) project for molecular sarcoma diagnosis with the aim of developing and validating DNA probes for in situ hybridization detection of translocations and their associated chromosomal breaks on the one hand, and DNA chips for the detection of fusion transcripts on the other. Research projects relate to the analysis of specific biomarkers in large tumor collectives and the pathomechanisms in several sarcoma entities.

Neues aus dem Jenaer Weichteiltumor-Register

The Jena Institute of Pathology has been serving as a consultation and reference center for soft tissue tumors in Germany since 1978. The present study provides an overview of the clinicopathological data from a two-year period and an update on diagnostics and research. Retrospectively, 7043 cases sent to the institute in the years 2006 and 2007 were analyzed. The majority of cases (>77.7%) were soft tissue tumors, of which 49% were categorized as malignant, 11.4% as intermediate, 35% as benign and 4.6% as tumors of uncertain biological potential. Neoplasms with fibroblastic differentiation were the most frequent. The mean age of patients with a sarcoma was 63 years. The molecular pathological analysis of soft tissue tumors has attained a major role in diagnosis. This is further advanced at the Jena institute in the context of a German Federal Ministry of Education and Research (BMBF) project for molecular sarcoma diagnosis with the aim of developing and validating DNA probes for in situ hybridization detection of translocations and their associated chromosomal breaks on the one hand, and DNA chips for the detection of fusion transcripts on the other. Research projects relate to the analysis of specific biomarkers in large tumor collectives and the pathomechanisms in several sarcoma entities.

Tyrosine kinases in soft tissue tumors

The development of therapeutic agents that specifically target the molecular alterations critical for tumorigenesis has a tremendous impact on the management of cancer patients. The successful treatment of advanced gastrointestinal stromal tumors (GIST) with receptor tyrosine kinase (RTK) inhibitors has raised the hope that other malignancies could also benefit from a similar treatment. Tyrosine kinase receptors are promising targets for personalized medicine and new drugs are currently in phase 2 and phase 3 clinical trials. We analyzed a large cohort of soft tissue sarcomas for different tyrosine kinase receptors and correlated the results with clinicopathological parameters. A total of 275 soft tissue sarcomas from the Ludwig-Maximilians University (LMU) were revisited and catagorized according to the current World Health Organization (WHO) classification system. Different entities showed distinct survival curves in 10-year long-term survival. Furthermore, different subtypes of sarcomas showed distinct expression profiles at the protein level. The expression of vascular endothelial growth factor (VEGF) receptors is associated with tumor progression. Due to the fact that not all patients respond to RTK inhibitor therapy, protein signatures should be evaluated before targeting therapy to give a rationale for a viable personalized therapy.

Elevated interferon-induced protein with tetratricopeptide repeats 3 (IFIT3) is a poor prognostic marker in pancreatic ductal adenocarcinoma

PurposeInterferon-induced protein with tetratricopeptide repeats 3 (IFIT3) gene from IFITs family is one gene among hundreds of IFN-stimulated genes. The potential role of IFIT3 in cancer is scarcely understood. In addition, the clinical relevance of IFIT3 is not yet known in pancreatic ductal adenocarcinoma (PDAC). We evaluated the prognostic significance of this gene in PDAC patients.MethodsThe expression of IFIT3 was analyzed in pancreatic cancer cell lines with different metastatic potential (FG and L3.6pl) and one established gemcitabine resistant cell variant-L3.6plGres. Second, we analyzed the protein expression in tissue microarrays (TMA) from specimens of 254 radically resected patients with pancreatic adenocarcinoma. The prognostic relevance of IFIT3 was evaluated by the Kaplan–Meier and Cox regression analysis.ResultsL3.6pl cells with an aggressive capacity showed a significant higher expression of IFIT3 as compared to FG cells. IFIT3 was accumulated in gemcitabine resistant cells. Overexpression of IFIT3 increased the resistance of apoptosis against gemcitabine treatment. Patients who had high expression of IFIT3 (32%) and received chemotherapy had a statistically significant reduced survival in multivariate analysis.ConclusionsHigh expression of IFIT3 enhances anti-apoptotic activity and chemotherapy resistance of PDAC cells. High expression of IFIT3 was independently correlated to shorter patients’ survival and may serve as a prognostic marker.

Tyrosinkinasen in Weichgewebstumoren

The development of therapeutic agents that specifically target the molecular alterations critical for tumorigenesis has a tremendous impact on the management of cancer patients. The successful treatment of advanced gastrointestinal stromal tumors (GIST) with receptor tyrosine kinase (RTK) inhibitors has raised the hope that other malignancies could also benefit from a similar treatment. Tyrosine kinase receptors are promising targets for personalized medicine and new drugs are currently in phase 2 and phase 3 clinical trials. We analyzed a large cohort of soft tissue sarcomas for different tyrosine kinase receptors and correlated the results with clinicopathological parameters. A total of 275 soft tissue sarcomas from the Ludwig-Maximilians University (LMU) were revisited and catagorized according to the current World Health Organization (WHO) classification system. Different entities showed distinct survival curves in 10-year long-term survival. Furthermore, different subtypes of sarcomas showed distinct expression profiles at the protein level. The expression of vascular endothelial growth factor (VEGF) receptors is associated with tumor progression. Due to the fact that not all patients respond to RTK inhibitor therapy, protein signatures should be evaluated before targeting therapy to give a rationale for a viable personalized therapy.

Erratum to: FGFR1 expression and gene copy numbers in human lung cancer

There was an error in the original version of Fig. 7 representing the DNA imbalances of the 4 lung cancer subtypes as detected by conventional CGH. For large cell lung cancer (LCLC), the ideogram of chromosome 9 together with the histograms of DNA gains and losses was shown and not chromosome 8 harbouring the FGFR1 locus. The corrected version with the chromosome 8 histogram (see new figure), however, indicates an identical finding, i.e. that chromosome 8p is more often affected by deletions than DNA gains.

Neues aus dem Jenaer Weichteiltumor-Register@@@Update from the soft tissue tumour registry in Jena

The Jena Institute of Pathology has been serving as a consultation and reference center for soft tissue tumors in Germany since 1978. The present study provides an overview of the clinicopathological data from a two-year period and an update on diagnostics and research. Retrospectively, 7043 cases sent to the institute in the years 2006 and 2007 were analyzed. The majority of cases (>77.7%) were soft tissue tumors, of which 49% were categorized as malignant, 11.4% as intermediate, 35% as benign and 4.6% as tumors of uncertain biological potential. Neoplasms with fibroblastic differentiation were the most frequent. The mean age of patients with a sarcoma was 63 years. The molecular pathological analysis of soft tissue tumors has attained a major role in diagnosis. This is further advanced at the Jena institute in the context of a German Federal Ministry of Education and Research (BMBF) project for molecular sarcoma diagnosis with the aim of developing and validating DNA probes for in situ hybridization detection of translocations and their associated chromosomal breaks on the one hand, and DNA chips for the detection of fusion transcripts on the other. Research projects relate to the analysis of specific biomarkers in large tumor collectives and the pathomechanisms in several sarcoma entities.